Both type 1 and type 2 diabetes can lead to diabetic nephropathy (DN), a serious microvascular complication. Bromodomain 4 (BRD4), a member of the BET protein family, has been linked to various diseases, including cancer, inflammation, and fibrosis, and may be involved in the development of diabetes and its complications. In this study, we first explored the role and mechanism of BRD4 in DN. We found that BRD4 expression was upregulated in both diabetic cells and animal models, and that BRD4 knockdown alleviated DN. Therefore, we next investigated the effect of AT1, a small-molecule degrader of BRD4 based on proteolysis targeting chimera (PROTAC) technology, on DN improvement. PROTAC has seldom been applied to non-oncological diseases, and this study represents the first application of AT1 to DN. Finally, we explored the molecular mechanisms underlying DN improvement.

中文翻译：

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AT1 是一种基于蛋白水解靶向嵌合体技术的 BRD4 小分子降解剂，可缓解糖尿病肾病中的肾纤维化和炎症


1 型和 2 型糖尿病都可能导致糖尿病肾病 （DN），这是一种严重的微血管并发症。溴结构域 4 （BRD4） 是 BET 蛋白家族的一员，与多种疾病有关，包括癌症、炎症和纤维化，并且可能与糖尿病及其并发症的发展有关。在这项研究中，我们首先探讨了 BRD4 在 DN 中的作用和机制。我们发现 BRD4 表达在糖尿病细胞和动物模型中均上调，BRD4 敲除减轻了 DN。因此，我们接下来研究了 AT1 对 DN 改善的影响，AT1 是一种基于蛋白水解靶向嵌合体 （PROTAC） 技术的 BRD4 小分子降解剂。PROTAC 很少应用于非肿瘤疾病，本研究是 AT1 在 DN 上的首次应用。最后，我们探讨了 DN 改善的分子机制。